DESCRIPTION: The cAMP signal transduction system may play an important role in the development of alcohol sm. The long-term goal of this research is twofold: 1) To elucidate the molecular and cellular mechanisms underlying ethanol's effects on the cAMP signaling pathway in the central nervous system, and 2) To determine the role that the cAMP signaling pathway plays in the physiological and behavioral responses to alcohol abuse. If a change in cAMP signaling is one of the determinants of an alcoholic phenotype, it is conceivable that alterations in the cAMP signaling system in an animal model may change the animal's response to ethanol. The hypothesis to be evaluated is that the response of animals to ethanol can be altered by the modification of adenylyl cyclase (AC) expression. To test this hypothesis, transgenic mice that overexpress type VII AC (AC7: the most ethanol sensitive isoform) and knockout mice that lack expression of AC7 will be generated. Once changes in the expression of AC7 are confirmed, the ethanol sensitivity of AC activity in the brain of the mutant mice will be examined. Ethanol's effect on the firing rate of the cerebellar Purkinje neurons of the mutant mice will be examined by electrophysiological recording. The sensitivity of the mutant mice to acute ethanol intoxication will be examined by measuring the duration of loss of righting reflex (sleep time) and the changes in body temperature (hypothermia). The development of tolerance in the mutant mice chronically treated with ethanol will be examined by measuring the decrease in the hypnotic and hypothermic effects of ethanol. The development of physical dependence in the mutant mice to ethanol will be examined by assessing the intensity of handling-induced convulsions after ethanol withdrawal. The proposed studies will generate valuable animal models for alcoholism research. These animals will also be useful for a wide-range of physiological and behavioral research dealing with cAMP signal transduction. The proposed studies will also provide information critical to the determination of whether abnormal cAMP signaling is one of the determinants of an alcoholic phenotype.